CN114478256B - 一种新型姜黄素衍生物的制备方法及其抗肝癌的应用 - Google Patents
一种新型姜黄素衍生物的制备方法及其抗肝癌的应用 Download PDFInfo
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Abstract
本发明提供了一种姜黄素衍生物的制备方法和其抗肝癌的应用,属于药物化学技术领域,本发明提供的姜黄素衍生物对肝癌细胞株HepG2具有抑制作用,通过诱导细胞凋亡而杀死癌细胞,本发明提供的姜黄素衍生物5e,生物利用率高,可将其用于制备抗肝癌的药物。本发明提供的姜黄素衍生物的制备方法制备得到的姜黄素衍生物纯度可达99%以上。
Description
技术领域
本发明属于医药技术领域,具体涉及一种姜黄素衍生物及其药学上可接受的盐或载体,以及该类化合物用于治疗肝癌的应用。
背景技术
世界卫生组织国际癌症研究机构(IARC)发布的最新《世界癌症报告》显示全球癌症新发病例达到1929万,癌症死亡996万人,其中肝癌死亡人数位居全球第三。肝癌是导致癌症相关死亡的三大原因之一,国内外研究人员开展了部分新型抗肝癌药物的研发工作,特别是从传统的中草药中寻找新型抗肝癌活性分子,这是抗肝癌新药研究领域的重要思路之一。这不仅能有效地挖掘出一大批有效的中药活性成分,也能够为“老药新用”概念提供理论基础。此外,基于中医药的重要研究成果开发新机制、新靶点、新结构的抗肝癌药物对我国中医药领域的进一步发展具有重要意义。
姜黄素是姜黄的主要活性成分之一,是一种含二苯基烯和二酮结构单元的黄色多酚类提取物。姜黄素一直被广泛用于色素、食品添加剂及调味品。研究显示,姜黄素具有抗肿瘤、抗炎、抗氧化等多种药理作用。近年来,姜黄素的抗肿瘤效果日益引起人们的重视,它对多种肿瘤细胞的产生、增殖和转移均有抑制作用,如肝癌、肺癌等。同时临床I和Ⅱ期试验已经证明姜黄素具有很好的安全性,美国国立肿瘤研究所已将其列为第三代癌化学预防药。
但是在临床实际应用中,姜黄素还存在一定的缺陷,如体内溶解度低、稳定性差、代谢过快、半衰期较短、生物利用度低、需要多次长时间口服等,从而限制了其在医药学方面的作用。因此,在保持姜黄素原有药效的基础上合成新型姜黄素类衍生物,从而提高生物利用度就成了研究的热点。
发明内容
有鉴于此,本发明目的在于提供一类姜黄素衍生物的制备方法及其抗肝癌的应用,本发明提供的姜黄素衍生物的抗肝癌活性强和生物利用度高。
本发明提供了一种具有如下通式所示结构的姜黄素衍生物:
所述R为F或Cl或CF3或NO2或CH3,取代位置为邻位或间位或对位。
本发明提供了上述具有通式所示结构的姜黄素衍生物的制备方法,包括以下步骤:
1、将化合物1和丙酮(2)溶解于无水乙醇,慢慢滴加氢氧化钠溶液,直至反应液颜色由白色变成淡黄色,发生醛酮缩合反应24h,后处理得到中间体化合物3。
2、先将不同的肉桂酸与氯化亚砜反应得到肉桂酰氯,然后在0度下慢慢滴加到含有中间体化合物3和三乙胺的氯仿溶液中,进行亲核取代反应12h,后处理得到七种姜黄素衍生物(com 5a-5g),其中抗肝癌活性最强的姜黄素衍生物为5e,具体结构如下:
本发明所获得的姜黄素类衍生物5e,具有非常优秀的抗癌作用,与姜黄素相比,本发明的IC50的浓度更低。
研究表明导致姜黄素生物利用度低的原因主要有以下两个方面:一方面β-二酮结构是导致姜黄素不稳定、代谢过快和生物利用度低的主要原因之一。通过对姜黄素的β-二酮结构进行了一系列的改造,以改善溶解性和稳定性进而提高其口服生物利用度。另一方面,由于姜黄素结构的二个酚羟基的存在,姜黄素口服后容易被代谢为姜黄素葡萄醣苷酸和姜黄素硫酸盐,并可转移到肠道以外的部位,并且该代谢物容易被清除,导致姜黄素的半衰期非常短,从而加速代谢和降低生物利用度。所以可以通过对裸露羟基的修饰进而改善口服生物利用度。
针对姜黄素的不足之处,本发明具体设计思路如下:一方面将β-二酮结构改造为单酮结构,提高稳定性进而提高生物利用度;另一方面在裸露的羟基上引入肉桂酸等天然活性分子,降低代谢速度和提高溶解度进而提高生物利用度,起到协同增效的作用。其中肉桂酸(又名桂皮酸),也是一种重要的天然活性分子,是从肉桂皮或安息香分离出的有机酸,具有抗肿瘤等多种生物活性。
本发明创新之处在于将两种具有抗肿瘤活性的生物分子,即姜黄素类和肉桂酸类化合物,利用孪药设计的化学方法有机结合在一起,获得更高活性和更好生物利用度的新型生物活性化合物。
附图说明
图1姜黄素衍生物5e的氢谱图
图2姜黄素衍生物5e的碳谱图
图3浓度为40μM下姜黄素衍生物5a-5g处理HepG2细胞48小时的抑制率
图4不同浓度下姜黄素衍生物5e处理HepG2细胞48小时的抑制率
图5不同浓度下姜黄素衍生物5e的克隆形成能力
图6不同浓度下姜黄素衍生物5e处理细胞0h、24h、48h后划痕愈合实验
图7不同浓度下姜黄素衍生物5e的线粒体膜电位实验
图8不同浓度下姜黄素衍生物5e的蛋白印迹实验
具体实施方法
现结合实施例和附图对本发明作进一步描述:
实施例1(1E,4E)-1,5-双(4-羟基-3-甲氧基苯基)戊-1,4-二烯-3-酮(com 3)的制备
将3-甲氧基4-羟基-苯甲醛(1.52g,10mmol)溶解于10mL无水乙醇中,然后加入3mL丙酮,再慢慢滴加2mol/L的氢氧化钠溶液,直至反应液颜色由白色变成淡黄色,继续室温反应24h,TLC法检测反应,用2mol/L的盐酸溶液调节pH至弱酸性,用乙酸乙酯萃取三遍,萃取相依次用饱和的氯化铵溶液和卤水洗涤,无水硫酸镁干燥,抽滤浓缩,残渣用乙酸乙酯和石油醚(体积比为1:2)为洗脱剂,硅胶柱层析分离纯化得到浅黄色粉末,产率约为45%。质谱、熔点和核磁图如下:
ESI-MS m/z:325.35(M-H)-.M.P.:128-130.1H NMR(400MHz,DMSO-d6)δ9.62(s,1H),7.52(d,J=16.3Hz,1H),7.30(s,1H),7.13(d,J=8.2Hz,1H),6.81(d,J=8.1Hz,1H),6.67(d,J=16.2Hz,1H),3.82(s,3H).13C NMR(101MHz,DMSO-d6)δ197.80,149.39,147.95,143.93,125.85,124.33,123.24,115.62,111.26,55.66.
实施例2(1E,4E)-1,5-双(4-羟基-3-甲氧基苯基)戊-1,4-二烯-3-酮的制备
将肉桂酸类化合物(1mmol)加至氯化亚砜(3mL)中,回流1h,TLC法检测反应完毕,减压蒸馏除去多余的氯化亚砜,得到黄色油状物即为肉桂酰氯(4a-4g)。在0℃下,化合物3(100mg,0.3mmol)溶于氯仿(10mL)中,并加入0.2mL的三乙胺作为缚酸剂,然后加入新鲜制备的肉桂酰氯,继续反应12h,TLC法检测反应完毕,减压旋干,残渣用乙酸乙酯和石油醚(体积比为1:3)为洗脱剂,硅胶柱层析分离纯化得到白色粉末5a-5g,产率约为55%到65%。质谱、熔点和核磁图如下:
(1)姜黄素衍生物5a
ESI-MS m/z:621.62(M-H)-.M.P.:145-148.1H NMR(400MHz,DMSO-d6)δ7.93–7.84(m,6H),7.63(d,J=16.4Hz,2H),7.53(s,2H),7.31(q,J=8.4Hz,6H),7.23(d,J=8.1Hz,2H),6.90(d,J=5.0Hz,2H),6.85(d,J=4.7Hz,2H),3.84(s,6H).13C NMR(101MHz,DMSO-d6)δ198.13,164.83,164.15,162.35,151.28,145.51,142.63,140.96,133.52,131.18,131.10,130.50,127.55,123.37,121.67,116.58,116.15,115.93,111.95,55.98.
(2)姜黄素衍生物5b
ESI-MS m/z:654.12(M-H)-.M.P.:153-156.1H NMR(400MHz,DMSO-d6)δ7.95–7.85(m,4H),7.64(d,J=16.3Hz,2H),7.59–7.51(m,6H),7.47–7.39(m,6H),7.25(s,2H),6.89(d,J=16.4Hz,2H),3.85(s,6H).13C NMR(101MHz,DMSO-d6)δ198.14,167.16,163.83,151.20,142.60,141.21,140.80,138.68,134.02,133.67,133.56,132.42,131.85,131.68,131.32,130.10,129.95,128.61,128.24,127.89,127.77,127.63,123.34,122.32,121.67,119.77,112.00,56.04.
(3)姜黄素衍生物5c
ESI-MS m/z:621.18(M-H)-.M.P.:117-120.1H NMR(400MHz,DMSO-d6)δ7.97(t,J=7.6Hz,2H),7.89(d,J=16.2Hz,2H),7.63(d,J=16.3Hz,2H),7.53(s,4H),7.32(p,J=7.9,7.0Hz,6H),7.25(s,2H),6.91(dd,J=24.0,16.3Hz,4H),3.84(s,6H).
(4)姜黄素衍生物5d
ESI-MS m/z:721.64(M-H)-.M.P.:110-112.1H NMR(400MHz,DMSO-d6)δ8.03(d,J=8.1Hz,4H),7.94(d,J=16.1Hz,2H),7.80(d,J=8.3Hz,4H),7.63(d,J=16.3Hz,2H),7.53(d,J=1.7Hz,2H),7.33(dd,J=8.2,1.7Hz,2H),7.24(d,J=8.1Hz,2H),7.05(d,J=16.1Hz,2H),6.88(d,J=16.4Hz,2H),3.84(s,6H).
(5)姜黄素衍生物5e
ESI-MS m/z:675.17(M-H)-.M.P.:154-156.1H NMR(400MHz,DMSO-d6)δ7.82(d,J=16.0Hz,2H),7.70(d,J=8.1Hz,4H),7.63(d,J=16.4Hz,2H),7.52(d,J=1.8Hz,2H),7.33(dd,J=8.2,1.8Hz,2H),7.27(d,J=8.0Hz,4H),7.22(d,J=8.1Hz,2H),6.88(d,J=16.4Hz,2H),6.82(d,J=16.0Hz,2H),3.83(s,6H).13CNMR(101MHz,DMSO-d6)δ198.15,163.93,162.02,159.51,151.23,142.61,140.85,138.41,133.64,129.64,127.60,125.16,123.34,121.66,116.30,116.08,111.99,56.02.
(6)姜黄素衍生物5f
ESI-MS m/z:675.63(M-H)-.M.P.:152-155.1H NMR(400MHz,DMSO-d6)δ8.28(d,J=8.8Hz,4H),8.11(d,J=8.8Hz,4H),7.98(d,J=16.1Hz,2H),7.64(d,J=16.4Hz,2H),7.54(d,J=1.7Hz,2H),7.35(dd,J=8.2,1.7Hz,2H),7.26(d,J=8.1Hz,2H),7.13(d,J=16.1Hz,2H),6.89(d,J=16.4Hz,2H),3.84(s,6H).
(7)姜黄素衍生物5g
ESI-MS m/z:613.69(M-H)-.M.P.:147-149.1H NMR(400MHz,DMSO-d6)δ7.95(s,2H),7.85(d,J=16.1Hz,2H),7.79(d,J=7.5Hz,2H),7.63(d,J=16.3Hz,2H),7.54–7.46(m,6H),7.35(d,J=1.7Hz,2H),7.24(d,J=8.1Hz,2H),7.00(d,J=16.1Hz,2H),6.88(d,J=16.4Hz,2H),3.84(s,6H).
实施例3抗肝癌效应和分子机制研究
(1)细胞增殖能力:将对数生长期的肝癌细胞(HepG2细胞)以3000个细胞/孔接种于96孔板,在含10%FBS的DMEM培养基中培养。待细胞贴壁后,姜黄素及其衍生物5a-5g(40μM)分别处理细胞48h,添加20μLMTT(4mg/mL)孔于37℃继续培养4h,每孔更换为200μLDMSO室温震荡10min,酶标仪上于570nm读取光密度,结果如图3所示,根据实验结果,筛选出衍生物5e的抑制率最高。
如图4所示,然后根据以上MTT法测定不同浓度(3.125,6.25,12.5,25,50,100μM)的姜黄素及其衍生物5e的细胞活力。抑制率(%)计算公式:1-[(OD实验组-OD空白组)/(OD对照组-OD空白组)×100%。利用GraphPad Prism 8软件非线性拟合得到IC50。实验结果至少通过三次实验获得。细胞增殖能力实验结果表明姜黄素和5e的IC50值分别为54.72±7.03和37.76±5.07μM。
(2)克隆形成能力,如图5所示:将对数生长期的HepG2细胞以1000个/孔的量接种在6孔板中,细胞过夜培养后,不同浓度(0,0.5,1,1.5μM)的姜黄素衍生物5e分别处理细胞48h。更换新鲜培养基,并将细胞继续在37℃下培养至形成肉眼可见的细胞集落。4%多聚甲醛固定并用结晶紫染色15min。根据克隆的数量和大小评估药物抗增殖效应差异。克隆形成能力实验结果表明5e具有明显的抗增殖能力和浓度依赖性。
(3)细胞迁移能力,如图6所示:将对数生长期细胞接种在6孔板中,过夜培养至细胞汇合度达100%,垂直于孔板底部划痕。1×PBS清洗三次,换用无FBS培养基,不同浓度(0,5,10,15μM)的姜黄素衍生物5e处理细胞。放入37℃、5%CO2培养箱中培养,按0h、24h、48h进行拍照。细胞划痕愈合实验结果表明5e具有明显的抗迁移能力,并且具有时间依赖性和浓度依赖性。
(4)线粒体膜电位如图7所示:将对数生长期细胞接种于24孔板,培养过夜,待细胞贴壁后,分组处理。吸弃培养液,PBS洗3遍,每次2分钟,每孔加500ul 10μg/mL的JC-1培养液,恢复至室温,轻摇混匀。细胞在37℃孵育15-20分钟。孵育结束后,吸弃上清,用PBS洗涤2次。加入500uL的PBS,用荧光显微镜观察JC-1聚合物红色荧光强度与JC-1单体绿色荧光强度。线粒体膜电位实验结果表明5e处理细胞以后,出现绿色荧光说明线粒体膜电位下降。随着5e的浓度增大,绿色荧光强度逐渐增大,红色荧光强度逐渐减小,说明5e具有明显的促凋亡能力和浓度依赖性。
(5)蛋白质印迹检测分子机制,如图8所示
制备不同浓度(0,5,10,15μM)的姜黄素衍生物5e处理组的全细胞裂解液,经蛋白质定量后,变性蛋白。将校正好的蛋白裂解物于SDS-PAGE中电泳后转移到PVDF膜上,脱脂牛奶中封闭1h后,将膜分别与目标蛋白一抗在4℃孵育过夜,对应二抗在室温下孵育1h。通过化学发光染色来检测Caspase 3、Caspase9、Bax、Bcl-2等关键促凋亡蛋白水平和磷酸化水平。蛋白质印迹实验结果表明5e处理细胞以后,Caspase 3、Caspase 9、Bax和Bcl-2的蛋白水平逐渐上升,再一次证明5e具有明显的促凋亡能力和浓度依赖性。
由以上实施例的测试结果可知,本发明采用孪药设计的化学方法进行姜黄素的结构修饰,通过两步简单的合成制备方法和一系列的药理实验(细胞增殖能力、克隆形成能力、迁移能力、线粒体膜电位以及蛋白质印迹),获得了一种具有明显抗肝癌活性的衍生物5e。
Claims (6)
1.一种姜黄素类衍生物,其特征在于,结构式如com5e所示:
。
2.根据权利要求1所述的姜黄素类衍生物的制备方法,其特征在于,包括以下步骤:先将间硝基肉桂酸与氯化亚砜反应得到间硝基肉桂酰氯,然后与如com3所示的结构式进行反应,
com3。
3.根据权利要求2所述的姜黄素类衍生物的制备方法,其特征在于,所述的反应条件为将间硝基肉桂酰氯在0度下慢慢滴入到含有com3和有机碱的氯仿溶液中,进行亲核取代反应。
4.根据权利要求3所述的姜黄素类衍生物的制备方法,其特征在于,所述的亲核取代反应的温度为室温。
5.根据权利要求4所述的姜黄素类衍生物的制备方法,其特征在于,所述的com3的制备方式为将
与丙酮进行醛酮缩合反应。
6.一种根据权利要求1所述的姜黄素类衍生物在制备抗肝癌药物中的应用。
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